Development of a common carp (Cyprinus carpio) pregnane X receptor (cPXR) transactivation reporter assay and its activation by azole fungicides and pharmaceutical chemicals

Lange, Anke; Corcoran, Jenna; Miyagawa, Shinichi; Iguchi, Taisen; Winter, Matthew J.; Tyler, Charles R.

doi:10.1016/j.tiv.2017.02.023

Cited by 13 publications

(18 citation statements)

References 53 publications

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“…Crystallization of zfPXR in complex with steroids and mutagenesis of the main amino acids in contact with the steroids in the zfPXR pocket would enable to confirm this selectivity. We also showed that the synthetic glucocorticoid dexamethasone and the pregnane pregnenolone 16a-carbonitrile, which are mouse PXR agonists, do not modulate zfPXR in accordance with what was previously reported with carp and zebrafish receptors (6,8,27).…”

Section: Discussionsupporting

confidence: 91%

“…The PGL4.24-6xPXRE reporter plasmid ( 6 ) is a kind gift from Anke Lange and Charles Tyler. The PXRE6-TATA-luciferase-hygromycin was constructed by adding the hygromycin resistance in this plasmid.…”

Section: Methodsmentioning

confidence: 99%

“…Several studies also highlighted its role in bone homeostasis, inflammation, drug-drug interaction, cancer drug resistance and proliferation in humans (2). In fish, although PXR role remains unclear, recent investigations reported its involvement in the regulation of P450 genes and revealed a crosstalk between zebrafish Aryl Hydrocarbon Receptor (AhR) and PXR, suggesting a role in the detoxification of xenobiotics in addition to bile salt metabolism (3)(4)(5)(6). Thus, modulation of fish PXR could affect their ability to eliminate adverse chemicals.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Comparative Study of Human and Zebrafish Pregnane X Receptor Activities of Pesticides and Steroids Using In Vitro Reporter Gene Assays

et al. 2021

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The nuclear receptor pregnane X receptor (PXR) is a ligand-dependent transcription factor that regulates genes involved in xenobiotic metabolism in mammals. Many studies suggest that PXR may play a similar role in fish. The interaction of human PXR (hPXR) with a variety of structurally diverse endogenous and exogenous chemicals is well described. In contrast, little is known about the zebrafish PXR (zfPXR). In order to compare the effects of these chemicals on the PXR of these two species, we established reporter cell lines expressing either hPXR or zfPXR. Using these cellular models, we tested the hPXR and zfPXR activity of various steroids and pesticides. We provide evidence that steroids were generally stronger activators of zfPXR while pesticides were more potent on hPXR. In addition, some chemicals (econazole nitrate, mifepristone, cypermethrin) showed an antagonist effect on zfPXR, whereas no antagonist chemical has been identified for hPXR. These results confirm significant differences in the ability of chemicals to modulate zfPXR in comparison to hPXR and point out that zfPXR assays should be used instead of hPXR assays for evaluating the potential risks of chemicals on aquatic species.

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Comparative Study of Human and Zebrafish Pregnane X Receptor Activities of Pesticides and Steroids Using In Vitro Reporter Gene Assays

et al. 2021

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“…Cell-based assays allow the study of the MoA of ligand-activated transcription factors (nuclear receptors) including PXR, PPARs, ERs and AhR (Raucy and Lasker, 2013;Puy-Azurmendi et al, 2014), which recognize a wide range of structurally-unrelated ligands acting as osteotoxicants. Recently, a transactivation reporter assay has been developed for the common carp (Cyprinus carpio) PXR and compared with the human isoform under the exposure to various fungicides and pharmaceuticals (Lange et al, 2017), further confirming the differential hability of tested compounds to activate fish and human PXR isoforms previously reported (Ekins et al, 2008).…”

Section: Fish Systems For Osteotoxicitysupporting

confidence: 62%

Fish as a model to assess chemical toxicity in bone

et al. 2018

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Environmental toxicology has been expanding as growing concerns on the impact of produced and released chemical compounds over the environment and human health are being demonstrated. Among the toxic effects observed in organisms exposed to pollutants, those affecting skeletal tissues (osteotoxicity) have been somehow overlooked in comparison to hepato-, immune-, neuro- and/or reproductive toxicities. Nevertheless, sub-lethal effects of toxicants on skeletal development and/or bone maintenance may result in impaired growth, reduced survival rate, increased disease susceptibility and diminished welfare. Osteotoxicity may occur by acute or chronic exposure to different environmental insults. Because of biologically and technically advantagous features - easy to breed and inexpensive to maintain, external and rapid rate of development, translucent larvae and the availability of molecular and genetic tools - the zebrafish (Danio rerio) has emerged in the last decade as a vertebrate model system of choice to evaluate osteotoxicity. Different experimental approaches in fish species and analytical tools have been applied, from in vitro to in vivo systems, from specific to high throughput methodologies. Current knowledge on osteotoxicity and underlying mechanisms gained using fish, with a special emphasis on zebrafish systems, is reviewed here. Osteotoxicants have been classified into four categories according to the pathway involved in the transduction of the osteotoxic effects: activation/inhibition of membrane and/or nuclear receptors, alteration of redox condition, mimicking of bone constituents and unknown pathways. Knowledge on these pathways is also reported here as it may provide critical insights into the development, production and release of future chemical compounds with none or low osteotoxicity, thus promoting the green/environmental friendly chemistry.

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“…cytochromes) in humans and is activated by a wide range of xenobiotics (e.g antibiotics) as well as endobiotics [63]. Activation of PXR has previously been observed by other azole fungicides such as miconazole and propiconazole [64] (see Fig. 7a, b).…”

Section: Knowtox-case Studymentioning

confidence: 69%

KnowTox: pipeline and case study for confident prediction of potential toxic effects of compounds in early phases of development

Morger¹,

Mathea²,

Achenbach³

et al. 2020

J Cheminform

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Risk assessment of newly synthesised chemicals is a prerequisite for regulatory approval. In this context, in silico methods have great potential to reduce time, cost, and ultimately animal testing as they make use of the ever-growing amount of available toxicity data. Here, KnowTox is presented, a novel pipeline that combines three different in silico toxicology approaches to allow for confident prediction of potentially toxic effects of query compounds, i.e. machine learning models for 88 endpoints, alerts for 919 toxic substructures, and computational support for read-across. It is mainly based on the ToxCast dataset, containing after preprocessing a sparse matrix of 7912 compounds tested against 985 endpoints. When applying machine learning models, applicability and reliability of predictions for new chemicals are of utmost importance. Therefore, first, the conformal prediction technique was deployed, comprising an additional calibration step and per definition creating internally valid predictors at a given significance level. Second, to further improve validity and information efficiency, two adaptations are suggested, exemplified at the androgen receptor antagonism endpoint. An absolute increase in validity of 23% on the in-house dataset of 534 compounds could be achieved by introducing KNNRegressor normalisation. This increase in validity comes at the cost of efficiency, which could again be improved by 20% for the initial ToxCast model by balancing the dataset during model training. Finally, the value of the developed pipeline for risk assessment is discussed using two in-house triazole molecules. Compared to a single toxicity prediction method, complementing the outputs of different approaches can have a higher impact on guiding toxicity testing and de-selecting most likely harmful development-candidate compounds early in the development process.

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Development of a common carp (Cyprinus carpio) pregnane X receptor (cPXR) transactivation reporter assay and its activation by azole fungicides and pharmaceutical chemicals

Cited by 13 publications

References 53 publications

A Comparative Study of Human and Zebrafish Pregnane X Receptor Activities of Pesticides and Steroids Using In Vitro Reporter Gene Assays

A Comparative Study of Human and Zebrafish Pregnane X Receptor Activities of Pesticides and Steroids Using In Vitro Reporter Gene Assays

Fish as a model to assess chemical toxicity in bone

KnowTox: pipeline and case study for confident prediction of potential toxic effects of compounds in early phases of development

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